The United States is under a genuine threat of biological attack. Whereas it has long been known that our enemies were capable of biological assault, only since September 2001 has it become clear that this threat is real. Unfortunately, the US is woefully unprepared to respond to biological attack. While rapid identification of released agents, novel therapeutic interventions and passive immunization will have vital roles to play in biodefense, there is no substitute for pre-existing immunity to the major threats. This immunity can either be provided before such agents are released, or can be provided soon after release has been detected. Unfortunately, for most infectious agents it is not currently feasible to provide rapid administration of vaccines that provide equally rapid protection. Moreover, it will be vital to ensure that any immunization program have both a high level of safety as well as public acceptance. We therefore envision a response strategy which includes live attenuated enteric bacterial vaccines. These vaccines would be very safe, and would elicit both mucosal and systemic responses. After just a single dose, they would protect many exposed to bioattack, and within one week of immunization. The protected would likely be those exposed to small or natural levels of exposure, such as postal workers handling contaminated mail. However, it is anticipated that some victims would be exposed to supra-normal inocula, typically by the aerosol or gastrointestinal routes. For these individuals, a protective vaccination regimen could include priming with the mucosal agent, followed by on-demand boosting with parenterally administered subunit vaccine. After boosting, the recipients would be expected to generate fast, vigorous, balanced immune responses, which would protect them at the level of the mucosa and via both Th1 and Th2 systemic components. This U19 will combine the vast experience of the University of Maryland School Center for Vaccine Development and the Chemical and Biological Defence Center, Porton Down in the development of enteric vaccines against anthrax, plague and botulism. The products developed will be tested in animals and the characteristics of prime-boost responses determined. During the term of the award, we will generate a series of vaccine candidates for immediate Phase 1 human trials.